A major challenge in the reconstruction of tooth-supporting alveolar bone defects is the simultaneous restoration of alveolar bone, cementum and a functional periodontal ligament (PDL). To date, major limitations exist with the predictability and extent of regeneration achievable via available regenerative periodontal therapies. Gene therapy has demonstrated strong potential to target, deliver, and improve bioavailability of growth-promoting factors (such as BMPs and PDGFs) to stimulate the re-engineering of periodontal defects. The goal of this competitive renewal is to exploit novel combinatorial gene delivery strategies and apply them to relevant models of oral and periodontal disease reconstructive modalities. Approaches will be employed to optimize gene transfer of growth promoting molecules using appropriate carrier delivery systems and vector constructs to repair relevant alveolar bone (tooth-supporting) defects. The specific aims of this proposal are: Specific Aim 1: To determine the ability of combinatorial gene delivery strategies to tissue engineer periodontal structures in an experimental periodontal disease model in rats as well as measure systemic biodistribution of gene therapy vectors in vivo. Specific Aim 2: To apply combinatorial gene delivery strategies using conventional and image-based scaffolding for regenerative medicine applications in experimental tooth- supporting bone defects in beagle dogs. Results from these studies will aid in the better understanding of sustained growth factor and gene delivery on periodontal wound repair. The long-term goal of this project will optimize and validate preclinical gene therapeutic approaches to provide sufficient evidence to consider application to human clinical conditions to repair large periodontal and oral and craniofacial bone defects.